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Despite the fact that anti-TNF alpha antibodies are well-tolerated and highly effective in Crohn's disease 25% to 40% of patients who initially benefited from the treatment are developing intolerable adverse events or are losing their response during maintenance therapy. The molecular mechanisms of loss of response are not fully understood, but clinicians face this clinical problem. The Aim of this paper is to review the clinical strategies to face loss of response to anti- TNF alpha antibodies in Crohn's disease.